1. Field of the Invention
The present invention relates to the general utility of AT4 receptor ligands to alter blood vessel growth (angiogenesis) in diseases associated with insufficient blood supply or those associated with excessive, undesired or inappropriate angiogenesis or proliferation of endothelial cells. In particular, AT4 receptor ligands that inhibit angiogenesis are extremely potent anti-cancer agents that block both the growth of primary tumors and the development of metastatic tumors.
2. Description of Related Art
The dominant therapeutic approaches that are currently employed to treat cancer include surgical removal of primary tumors, tumor irradiation, and parenteral application of anti-mitotic cytotoxic agents. The continued dominance of these long established therapies is mirrored by the lack of improvement in survival rates for most cancers. Improvements that have been observed can be traced not to therapeutic advancements but diagnostic ones. In addition to limited clinical success, devastating side effects accompany classic therapies. Both radiation- and cytotoxic-based therapies result in the destruction of rapidly dividing hematopoietic and intestinal epithelial cells leading to compromised immune function, anemia, and impaired nutrient absorption. Surgical intervention often results in a release of tumor cells into the circulation or lymph systems from which metastatic tumors can subsequently be established. Furthermore, primary tumors often produce or generate endogenous anti-angiogenic substances that suppress the growth of already established but undetected micrometastases (O'Reilly et al., 1994). Their removal, without accompanying treatment that is directed at the micrometastases often leads to rapid expansion of the metastatic tumors with fatal consequences.
Because of the shortcomings of classic treatment regimens several new approaches to cancer therapy have been initiated over the past decade. Most prominent among these are the development of vaccines directed at cancer cells (Morris et al., 2003), the related use of immunotoxins (antibodies linked to cytotoxic agents) (Pastan and Kreitman, 2002), hormone-based therapies (Kenemans and Bosman , 2003), and anti-angiogenics that are designed to limit tumor. growth and metastasis by inhibiting tumor vascularization (Kerbel and Folkman, 2002). Although, the vaccine and immunotoxin therapeutic approach has been under development for some time no immuno-based therapy is now in use as a standard cancer treatment. The utility of this approach is limited by two properties that are inherent to cancer cells. First, cancers are derived from many cell types all with different antigenic profiles. Therefore, each cancer type would necessarily require its own specific set of therapeutic reagents that would entail prohibitively expensive individual development. Second, the antigenic targets of the reagents would never be totally unique to the transformed cancer cells but would also be represented on normal healthy cells resulting in unwanted cytotoxic damage. Hormone-based therapies, while useful for the treatment of a select group of cancers, will never be a treatment option that is generally applicable to the vast majority of cancers that are hormone insensitive. The successful development of a new and generally useful cancer therapy must meet two critical criteria. First, the treatment must target a molecular target or process that is associated with most (if not all) cancers. Next, the treatment must have little or no impact on normal cells. Unlike immune- or hormone-based cancer therapies, anti-angiogenic-based therapies meet both of these criteria.
Neovasularization of tumors is requisite for both the growth and metastasis of tumors. The vascularization of tumor provides it with a dedicated source of nutrients and oxygen that are essential for continued growth. Without a dedicated blood supply the availability of nutrients and oxygen, which must be furnished by vessels external to the neoplasm, is diffusion limited restricting tumor size to about 1 millimeter in diameter. In addition to providing nutrients and oxygen, the tumor vasculature, which is often abnormally permeable, acts as a conduit enabling cancer cells to escape into the general circulation from whence they can establish metastatic tumors at distant sites. The inverse relationship between tumor vascularization and patient prognosis is well recognized and reflects the fact that 90% of cancer patients die of metastatic disease and not primary tumors. The realization that most, if not all, tumors require a dedicated blood supply in order to progress to a clinically relevant state spawned the notion that inhibiting tumor neovasularization could control cancer progression. This could be accomplished by blocking the process of angiogenesis in which vascular endothelial cells divide and migrate to produce branching of established vessels. A particularly attractive aspect of targeting angiogenesis is that the frequency of cancer is increased in older adults who possess quiescent endothelial cells with a normal turnover rate of 1000 days and occurs only during wound healing and menses. Thus, anti-angiogenic drugs meet the primary criteria for a general anti-cancer agent- i.e. broad applicability and minimal effects on normal tissues. Another advantage offered by anti-angiogenic drugs is that they target a cell population (endothelial cells) that is genetically stable and far less likely to support the development of drug resistance that is regularly seen with drugs directed at cancer cells. A final advantage offered by anti-angiogenics is their ready access to endothelial target cells following parenteral application.